Bicyclic amines and their use as insecticides

ABSTRACT

A compound of formula (I) wherein A is a bidentate group of the formula: XC═CY or XCH—CHY (wherein X and Y are independently hydrogen, hydroxy, acyloxy, alkoxy, cyano or halogen); and Ar is optionally substituted phenyl or optionally substituted heteroaryl; or an acid addition salt, quaternary ammonium salt or N-oxide derived therefrom; provided that when A is CH 2 —H 2  then Ar is neither 5-chloropyrid-3-yl nor 5-trifluoromethylpyrid-3-yl; an insecticidal, acaricidal or nematicidal composition comprising an insecticidally, acaricidally or nematicidally effective amount of a compound of formula (I); a method of using a compound of formula (I) to combat or control insect, acarine or nematode pests; and processes for preparing a compound of said formula.

This is a 371 of Application No. PCT/GB98/03098, filed Oct. 15, 1998.

This invention relates to bicyclic amine derivatives, to processes forpreparing them, to insecticidal compositions comprising them and tomethods of using them to combat and control insect pests.

Insecticidal bicyclic amines are disclosed in WO 96/37494.

The present invention provides a compound of formula (I):

wherein A is a bidentate group of formula XC═CY or XCH—CHY (wherein Xand Y are independently hydrogen, hydroxy, acyloxy, alkoxy, cyano orhalogen); and Ar is optionally substituted phenyl or optionallysubstituted heteroaryl; or an acid addition salt, quaternary ammoniumsalt or N-oxide derived therefrom; provided that when A is CH₂—CH₂ thenAr is neither 5-chloropyrid-3-yl nor 5-trifluoromethylpyrid-3-yl.

It will be appreciated that the compounds of formula (I) are capable ofexisting in more than one isomeric form since groups may be positionedin either an exo or endo relationship, and the present inventionembraces within its scope both exo and endo forms and mixtures thereofin all proportions and also any further isomeric variants arising fromcis and trans substitution patterns or chiral centres.

Heteroaryl includes 5- and 6-membered rings comprising one, two or threeheteroatoms selected form the group comprising nitrogen, oxygen andsulphur, said rings being optionally fused to a benzene ring. Examplesof heteroaryl are pyridine, pyrazine, pyridazine, pirimidine, pyrrole,pyrazole, imidazole, 1,2,3- and 1,2,4-triazoles, furan, thiophene,oxazole, isoxazole, thiazole, isothiazole, 1,2,3- and 1,3,4-oxadiazoles,1,2,3- and 1,3,4-thiadiazoles, benzoxazole, indole, benzofuran,benzothiophen and benzimidazole.

Halogen includes fluorine, chlorine, bromine and iodine.

Alkyl moieties preferably contain from 1 to 6, more preferably from 1 to4, carbon atoms. They can be in the form of straight or branched chains,for example methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- ortert-butyl.

Acyloxy is preferably alkylcarbonyloxy or optionally substitutedphenylcarbonyloxy. Acyloxy is, for example, acetyloxy or benzoyloxy.

Phenyl and heteroaryl rings are preferably optionally substituted with:halogen, hydroxy, mercapto, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy, halo(C₁₋₄)alkyl (for exampleCF₃), halo(C₁₋₄)alkoxy (for example OCF₃), C₁₋₄alkylthio,halo(C,₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl, C₁₋₄alkoxy(C₁₋₄)alkyl (forexample CH₃OCH₂), C₃₋₆cycloalkyl (such as cyclopentyl or cyclohexyl),C₃₋₆cycloalkyl(C₁₋₄)alkyl (such as cyclopentylmethyl or1-cyclopropyleth-1-yl), phenyl, phenoxy, SF₅, cyano, thiocyanato, nitro,—NR′R″, —NHCOR′, —CONR′R″, —COOR′, —SOR′, —SO₂R′, —SO₂(C₃₋₆)alkenyl,—OSO₂R′, —NHSO₂R′, —SO₂NR′R″, —COR′, —CR′═N″, —CR′═NOR″ or —N═CR′N″; twosubstituents, when they are in adjacent positions on the phenyl orheteroaryl ring can join to form a fused aliphatic ring (especially toform a fused 6-membered carbon aliphatic ring) or a fused alkylenedioxyring (such as methylenedioxy or difluoromethylenedioxy); R′ and R″ areindependently hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio,C₃₋₆cycloalkyl, C₃₋₆cycloalkyl(C₁₋₄)alkyl, phenyl or benzyl; the phenyl,phenoxy and benzyl groups being optionally substituted with halogen,C₁₋₄alkyl, halo(C₁₋₄)alkyl, C₁₋₄alkoxy or C₁₋₄haloalkoxy.

Alkenyl and alkynyl moieties can be in the form of straight or branchedchains, and alkenyl moieties can be of either (E)- or (Z)-configuration.Examples are vinyl, allyl and propargyl.

Suitable acid addition salts include those with an inorganic acid suchas hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, oran organic carboxylic acid such as oxalic, tartaric, lactic, butyric,toluic, hexanoic and phthalic acids, or sulphonic acids such as methane,benzene and toluene sulphonic acids. Other examples of organiccarboxylic acids include haloacids such as trifluoroacetic acid.

In one aspect the present invention provides a compound of formula (I)wherein A is CH₂—CH₂ or CH═CH.

In a further aspect the present invention provides a compound of formula(I) wherein A is CH═CH.

In another aspect the present invention provides a compound of formula(I), wherein Ar is phenyl or pyrazinyl, all being optionally substitutedwith halogen (especially fluorine, chlorine or bromine), C₁₋₄alkyl(especially methyl), C₁₋₄alkoxy (especially methoxy), C₂₋₄alkenyl,C₂₋₄alkynyl or cyano.

In a further aspect the present invention provides a compound of formula(I) wherein Ar is pyridinyl optionally substituted with fluorine,bromine, cyano, C₁₋₄alkyl, C₁₋₄alkoxy or C₂₋₄haloalkyl (such as2,2,2-trifluoroethyl, 2,2-difluoroethyl or 2,2,2-trichloroethyl).

Specific compounds of formula (I) are set out in the Tables below.

TABLE 1 Compound No. Ar A 1 5-chloropyrid-3-yl CH═CH 25-methoxypyrid-3-yl CH₂—CH₂ 3 5-bromopyrid-3-yl CH₂—CH₂ 43,5-difluorophenyl CH₂—CH₂ 5 5-trifluoromethylpyrid-3-yl CH═CH 65-methoxypyrid-3-yl CH═CH 7 5-bromopyrid-3-yl CH═CH 8 3,5-difluorophenylCH═CH 9 5-acetylenylpyrid-3-yl CH₂—CH₂ 10 5-acetylenylpyrid-3-yl CH═CH11 5-cyanopyrid-3-yl CH₂—CH₂ 12 5-cyanopyrid-3-yl CH═CH 136-methoxypyrazin-2-yl CH₂—CH₂ 14 6-methoxypyrazin-2-yl CH═CH 15pyrid-3-yl CH₂—CH₂ 16 pyrid-3-yl CH═CH 17 6-chloropyrazin-2-yl CH₂—CH₂18 6-chloropyrazin-2-yl CH═CH 19 3,5-dichlorophenyl CH₂—CH₂ 203,5-dichlorophenyl CH═CH

Compounds of formula (I) can be prepared by adapting methods describedin the literature (such as WO 96/37494), by use of one or more of thefollowing synthetic techniques described below and further illustratedin the Examples, or by combining literature methods with those methodsdescribed below. Throughout the following description R is alkyl (suchas methyl) or phenylalkyl (such as benzyl).

A compound of formula (I) can be prepared by reacting a compound offormula (II) with formic acid at an elevated temperature (such as over70° C.).

Alternatively, a compound of formula (I) can be prepared by reacting acompound of formula (II) with a suitable mixed formic anhydride (such asformic acetic anhydride).

A compound of formula (II) can be prepared by reacting a compound offormula (III) with a suitable chloroformate (such a vinyl chloroformate)and reacting the product so formed with a mineral acid (such asconcentrated hydrochloric acid).

A compound of formula (III) can be prepared by treating a compound offormula (IV) first with a suitable base, such as lithiumdiisopropylamide (LDA) or lithium bis(trimethylsilyl)amide, and thenreacting the product so formed with a compound ArHal, wherein Hal is ahalogen.

A compound of formula (IV) can be prepared by reacting a compound offormula (V) with a compound of formula RL (wherein L is a suitableleaving group, such as a halide) preferably in the presence of a base.

Compounds of formula (V) can be prepared by processes analogous to thosedescribed in the art.

Compounds of formula (III) wherein A is CH═CH can be prepared by heatinga compound of formula (III) wherein A is CH₂CHZ (wherein Z is a suitablegroup, such as a thiono4-tolyloxy group) in a suitable solvent (such asxylene) at a suitable temperature (such as reflux).

Compounds of formula (III) wherein A is CH₂CHZ (wherein Z is a suitablegroup, such as a thiono4-tolyloxy group) can be prepared by treatingcompounds of formula (III) wherein A is CH₂CH(OH) with a suitablethionoformate (such as 4-tolyl chlorothiono formate) in the presence ofa suitable base (such as NIN-dimethylaminopyridine).

Compounds of formula (III) wherein A is CH₂CH(OH) can be prepared byacid hydrolysis of compounds of formula (III) wherein A is CH₂CH(OZ′)wherein Z′ is a hydrolysable group (such as tert-butyldimethylsilyl).

A compound of formula (III) wherein A is CH₂CH(OZ′) wherein Z′ is ahydrolysable group (such as tert-butyldimethylsilyl) can be prepared byreacting a corresponding compound of formula (IV) with a suitable base,such as lithium diispropylamide (LDA) or lithiumbis(trimethylsilyl)amide, and reacting the product so formed with acompound ArHal, wherein Hal is a halogen.

A compound of formula (IV) wherein A is CH₂CH(OZ′) wherein Z′ is ahydrolysable group (such as tert-butyldimethylsilyl) can be prepared bytreating a corresponding compound of formula (VI) with tosylmethylisocyanide (also known as (4-tolylsulfonyl)methylisocyanide) in thepresence of a suitable base, such as potassium tert-butoxide.

A compound of formula (VI) wherein A is CH₂CH(OZ′) wherein Z′ is ahydrolysable group (such as tert-butyldimethylsilyl) can be prepared byreacting a compound of formula (VI) wherein A is CH₂CH(OH) with acompound Z′L wherein L is a leaving group.

A compound of formula (VI) wherein A is CH₂CH(OH) can be prepared byreacting 2,5-dimethoxy-2,5-dihydrofuran, acetone dicarboxylic acid andan amine of formula RNH₂ (which is preferably in the form of a salt,such as a hydrochloride salt).

Alternatively a compound of formula (III) wherein A is CH═CH can beprepared by dehydrating a compound of formula (III) wherein A isCH₂CH(OH) with a suitable dehydrating agent, such asdiethylaminosulfurtrifluoride.

A compound of formula (III) wherein A is CH₂CHF can be prepared byfluorinating a compound of formula (III) wherein A is CH₂CH(OH) with,for example, a mixture of hydrogen fluoride and sulfur trifluoride.

A compound of formula (III) wherein A is CH₂C(═O) can be prepared byreacting a compound of formula (III) wherein A is CH₂CH(OH) with asuitable oxidising agent at a suitable temperature.

A compound of formula (III) wherein A is CH₂CF₂ can be prepared byfluorinating a compound of formula (III) wherein A is CH₂C(═O) with, forexample, diethylamino-sulfurtrifluoride.

A compound of formula (III) wherein A is CH═CH can be prepared byreacting a compound of formula (III) wherein A is CH₂CH(OZ′), wherein Z′is a suitable group (such as SO₂CH₃) with a suitable amine (such as1,8-diazabicyclo[5.4.0]undec-7-ene).

A compound of formula (III) wherein A is CH₂CH(OZ′), wherein Z′ is asuitable group (such as SO₂CH₃) can be prepared by reacting a compoundof formula (III) wherein A is CH₂CH(OH) with a suitable acid chloride(such as mesyl chloride).

In further aspects the present invention provides processes forpreparing compounds of formula (I) as hereinbefore described.

In a further aspect the invention provides a method of combating insectand like pests at a locus by applying to the locus or the pests aninsecticidally effective amount of an insecticidal compositioncomprising a compound of formula (I) or an acid addition salt,quaternary ammonium salt or N-oxide derived therefrom.

The compounds of formula (I) can be used to combat and controlinfestations of insect pests such as Lepidoptera, Diptera, Homoptera andColeoptera (including Diabrotica i.e. corn rootworms) and also otherinvertebrate pests, for example, acarine pests. The insect and acarinepests which may be combated and controlled by the use of the inventioncompounds include those pests associated with agriculture (which termincludes the growing of crops for food and fibre products), horticultureand animal husbandry, forestry, the storage of products of vegetableorigin, such as fruit, grain and timber, and also those pests associatedwith the transmission of diseases of man and animals. Examples of insectand acarine pest species which may be controlled by the compounds offormula (I) include: Myzus persicae (aphid), Aphis iossvpii (aphid),Aphis fabae (aphid), Aedes aegypti (mosquito), Anopheles spp.(mosquitos), Culex spp. (mosquitos), Dysdercus fasciatus (capsid), Muscadomestica (housefly), Pieris brassicae (white butterfly), Plutellaxylostella (diamond back moth), Phaedon cochleariae (mustard beetle),Aonidiella spp. (scale insects), Trialeurodes spp. (white flies),Bemisia tabaci (white fly), Blattella germanica (cockroach), Periplanetaamericana (cockroach), Blatta orientalis (cockroach) Spodopteralittoralis (cotton leafworm), Heliothis virescens (tobacco budworm)Chortiocetes terminifera (locust), Diabrotica spp. (rootworms), Aerotisspp. (cutworms), Chilo partellus (maize stem borer), Nilaparvata lugens(planthopper), Nephotettix cincticeps (leafhopper), Panonychus ulmi(European red mite), Panonychus citri (citrus red mite), Tetranychusurticae (two-spotted spider mite), Tetranychus cinnabarinus (carminespider mite), Phyllcoptruta oleivora (citrus rust mite),Polyphagotarsonemus latus (broad mite) and Brevipalpus spp. (mites).Further examples include insects which adversely affect the health ofthe public or of animals.

In order to apply the compounds of formula (I) to the locus of thenematode, insect or acarid pest, or to a plant susceptible to attack bythe nematode, insect or acarid pest, the compound is usually formulatedinto a composition which includes in addition to a compound of formula(I) a suitable inert diluent or carrier material, and, optionally, asurface active agent. The amount of composition generally applied forthe control of nematode pests gives a rate of active ingredient from0.01 to 10 kg per hectare, preferably from 0.1 to 6 kg per hectare.

Thus in another aspect the present invention provides a insecticidal,acaricidal or nematicidal composition comprising an insecticidally,acaricidally or nematicidally effective amount of a compound of formula(I) and a suitable carrier or diluent therefor.

The compositions can be applied to the soil, plant or seed, to the locusof the pests, or to the habitat of the pests, in the form of dustingpowders, wettable powders, granules (slow or fast release), emulsion orsuspension concentrates, liquid solutions, emulsions, seed dressings,fogging/smoke formulations or controlled release compositions, such asmicroencapsulated granules or suspensions.

Dusting powders are formulated by mixing the active ingredient with oneor more finely divided solid carriers and/or diluents, for examplenatural clays, kaolin, pyrophyllite, bentonite, alumina,montmorillonite, kieselguhr, chalk, diatomaceous earths, calciumphosphates, calcium and magnesium carbonates, sulphur, lime, flours,talc and other organic and inorganic solid carriers.

Granules are formed either by absorbing the active ingredient in aporous granular material for example pumice, attapulgite clays, Fuller'searth, kieselguhr, diatomaceous earths, ground corn cobs, and the like,or on to hard core materials such as sands, silicates, mineralcarbonates, sulphates, phosphates, or the like. Agents which arecommonly used to aid in impregnation, binding or coating the solidcarriers include aliphatic and aromatic petroleum solvents, alcohols,polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters,dextrins, sugars and vegetable oils. with the active ingredient. Otheradditives may also be included, such as emulsifying agents, wettingagents or dispersing agents.

Microencapsulated formulations (microcapsule suspensions CS) or othercontrolled release formulations may also be used, particularly for slowrelease over a period of time, and for seed treatment.

Alternatively the compositions may be in the form of liquid preparationsto be used as dips, irrigation additives or sprays, which are generallyaqueous dispersions or emulsions of the active ingredient in thepresence of one or more known wetting agents, dispersing agents oremulsifying agents (surface active agents). The compositions which areto be used in the form of aqueous dispersions or emulsions are generallysupplied in the form of an emulsifiable concentrate (EC) or a suspensionconcentrate (SC) containing a high proportion of the active ingredientor ingredients. An EC is a homogeneous liquid composition, usuallycontaining the active ingredient dissolved in a substantiallynon-volatile organic solvent. An SC is a fine particle size dispersionof solid active ingredient in water. In use, the concentrates arediluted in water and applied by means of a spray to the area to betreated.

Suitable liquid solvents for ECs include methyl ketones, methyl isobutylketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins,kerosene, white oil, alcohols, (for example, butanol),methylnaphthalene, trimethylbenzene, trichloroethylene,N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (TBFA).

Wetting agents, dispersing agents and emulsifying agents may be of thecationic, anionic or non-ionic type. Suitable agents of the cationictype include, for example, quaternary ammonium compounds, for examplecetyltrimethyl ammonium bromide. Suitable agents of the anionic typeinclude, for example, soaps, salts of aliphatic monoesters of sulphuricacid, for example sodium lauryl sulphate, salts of sulphonated aromaticcompounds, for example sodium dodecylbenzenesulphonate, sodium, calciumor ammonium lignosulphonate, or butylnaphthalene sulphonate, and amixture of the sodium salts of diisopropyl- and triisopropylnaphthalenesulphonates. Suitable agents of the non-ionic type include, for example,the condensation products of ethylene oxide with fatty alcohols such asoleyl alcohol or cetyl alcohol, or with alkyl phenols such as octylphenol, nonyl phenol and octyl cresol. Other non-ionic agents are thepartial esters derived from long chain fatty acids and hexitolanhydrides, the condensation products of the said partial esters withethylene oxide, and the lecithins.

These concentrates are often required to withstand storage for prolongedperiods and after such storage, to be capable of dilution with water toform aqueous preparations which remain homogeneous for a sufficient timeto enable them to be applied by conventional spray equipment. Theconcentrates may contain 10-85% by weight of the active ingredient oringredients. When diluted to form aqueous preparations such preparationsmay contain varying amounts of the active ingredient depending upon thepurpose for which they are to be used.

The compounds of formula (I) may also be formulated as powders (dry seedtreatment DS or water dispersible powder WS) or liquids (flowableconcentrate FS, liquid seed treatment LS, or mnicrocapsule suspensionCS) for use in seed treatments.

In use the compositions are applied to the insect pests, to the locus ofthe pests, to the habitat of the pests, or to growing plants liable toinfestation by the pests, by any of the known means of applyingpesticidal compositions, for example, by dusting, spraying, orincorporation of granules.

The compound of formula (I) may be the sole active ingredient of thecomposition or it may be admixed with one or more additional activeingredients such as insecticides, synergists, herbicides, fungicides orplant growth regulators where appropriate. Suitable additional activeingredients for inclusion in admixture with a compound of formula (I)may be compounds which will broaden the spectrum of activity of thecompositions of the invention or increase their persistence in thelocation of the pest. They may synergise the activity of the compound offormula (I) or complement the activity for example by increasing thespeed of effect or overcoming repellency. Additionally multi-componentmixtures of this type may help to overcome or prevent the development ofresistance to individual components. The particular additional activeingredient included will depend upon the intended utility of the mixtureand the type of complementary action required. Examples of suitableinsecticides include the following:

a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin,cyhalothrin in particular lambda-cyhalothrin, biphenthrin,fenpropathrin, cyfluthrin, tefluthrin, fish safe pyrethroids for exampleethofenprox, natural pyrethrin, tetramethrin, s-bioallethrin,fenfluthrin, prallethrin and5-benzyl-3-firylmethyl-(E)-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate;

b) Organophosphates such as profenofos, sulprofos, methyl parathion,azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos,monocrotophos, profenophos, triazophos, methamidophos, dimethoate,phosphamidon, malathion, chloropyrifos, phosalone, terbufos,fensulfothion, fonofos, phorate, phoxim, pyrimiphos-methyl,pyrimiphos-ethyl, fenitrothion or diazinon;

c) Carbamates (including aryl carbamates) such as pirimicarb,cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb,thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl;

d) Benzoyl ureas such as triflumuron, or chlorfluazuron;

e) Organic tin compounds such as cyhexatin, fenbutatin oxide,azocyclotin;

f) Macrolides such as avermectins or milbemycins, for example such asabamectin, ivermectin, and milbemycin;

g) Hormones and pheromones;

h) Organochlorine compounds such as benzene hexachloride, DDT, chlordaneor dieldrin;

i) Amidines, such as chlordimeform or amitraz;

j) Fumigant agents;

k) Imidacloprid;

l) Spinosad.

In addition to the major chemical classes of insecticide listed above,other insecticides having particular targets may be employed in themixture if appropriate for the intended utility of the mixture. Forinstance selective insecticides for particular crops, for examplestemborer specific insecticides for use in rice such as cartap orbuprofezin can be employed. Alternatively insecticides specific forparticular insect species/stages for example ovo-larvicides such aschlofentezine, flubenzimine, hexythiazox and tetradifon, motilicidessuch as dicofol or propargite, acaricides such as bromopropylate,chlorobenzilate, or growth regulators such as hydramethylron,cyromazine, methoprene, chlorofluazuron and diflubenzuron may also beincluded in the compositions.

Examples of suitable synergists for use in the compositions includepiperonyl butoxide, sesamax, safroxan and dodecyl imidazole.

Suitable herbicides, fungicides and plant-growth regulators forinclusion in the compositions will depend upon the intended target andthe effect required.

An example of a rice selective herbicide which can be included ispropanil, an example of a plant growth regulator for use in cotton is“Pix”, and examples of fungicides for use in rice include blasticidessuch as blasticidin-S. The ratio of the compound of formula (I) to theother active ingredient in the composition will depend upon a number offactors including type of target, effect required from the mixture etc.However in general, the additional active ingredient of the compositionwill be applied at about the rate at which it is usually employed, or ata slightly lower rate if synergism occurs.

The invention is illustrated by the following Examples. Examples 1-4illustrate the preparation of a range of compounds of formula (I).Examples 5 to 12 illustrate compositions suitable for the application ofthe compounds of formula (I) according to the invention. The followingingredients are referred to by their Registered Trade Marks and have thecomposition as shown below.

Registered Trade Mark Composition Synperonic NP8 } Nonylphenol-ethyleneoxide Synperonic NP13 } condensate Synperonic OP10 } Aromasol HAlkylbenzene solvent Solvesso 200 Inert organic diluent KeltrolPolysaccharide

Selected NMR data and melting point data are presented in the Examples.For NMR data, no attempt has been made to list every absorption. Thefollowing abbreviations are used throughout the Examples:

mp = melting point (uncorrected) ppm = parts per million s = singlet t =triplet d = doublet q = quartet dd = double doublet brd = broad doubletm = multiplet

EXAMPLE 1

This Example illustrates the preparation ofexo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]oct-6-ene(Compound No. 1 I).

Stage 1

2,5-Dimethoxy-2,5-dihydrofuran (97.5 g) was dissolved in water (650 ml)and treated with aqueous hydrochloric acid (3.75 ml, 2M) under anatmosphere of nitrogen. The mixture was heated to 96° C. with stirringand aqueous methanol (about 100 ml) distilled from the reaction vesseluntil the reaction solution reached 98-99° C. The reaction was cooled toambient temperature, acetone dicarboxylic acid (146 g) added in oneportion followed by a solution of sodium hydrogen phosphate (53.25 g)and sodium hydroxide (15.0 g) in water (500 ml). 1,4-Dioxane (100 ml)was added and a solution of benzylamine hydrochloride (71.75 g) in water(330 ml) added dropwise over 10 minutes. The mixture was rapidly stirredfor a further 4 hours, acidified with aqueous hydrochloric acid (2M),dichloromethane (500 ml) added and the reaction mixture stirred for 10minutes. The aqueous phase was decanted from the residual brown gum,filtered through a bed of kieselguhr and the filtrate extracted withdichloromethane (3×500 ml). The aqueous phase was collected, basifiedwith potassium carbonate and extracted with ethyl acetate (3×1000 ml).The organic fractions were combined, dried (magnesium sulfate) andevaporated under reduced pressure to give a brown oil, 55 g, containinga mixture of exo- and endo-6-hydroxy-8-benzyl-8-azabicyclo[3.2.1]octan-3-one (ratio 7:1).

Stage 2

tert-Butyldimethylsilyl chloride (26.5 g) was dissolved inN,N-dimethylformamide (400 ml, dry) with stirring under an atmosphere ofnitrogen and imidazole (25.0 g) added in portions. The mixture wasstirred for 10 minutes and a solution of the product from Stage 1 (55 g)in N N-dimethylfonnamide (250 ml, dry) added in portions. The dark brownreaction mixture was stirred at ambient temperature for 3 hours, storedfor 18 hours and poured into water (2,500 ml). The product was extractedinto hexane (3×800 ml), the combined organic phases washed with water(2×1000 ml) and dried (sodium sulfate). The solvent was evaporated underreduced pressure to give a brown oil, 44.5 g, containing a mixture ofexo- and endo-6-tert-butyldimethylsilyloxy-8-benzyl-8-azabicyclo[3.2.1]octan-3-one (ratio 7:1).

Stage 3

The material from Stage 2 (44 g) in 1,2-dimethoxyethane (160 ml, dry)containing 4-tolylsulfonylmethylisocyanide (41 g) was added dropwiseover 1.5 hours to a mixture of potassium tert-butoxide (19.0 g) andsodium ethoxide (14.5 g) in 1,2-dimethoxyethane (140 ml, dry ) at 40° C.under an atmosphere of nitrogen. The mixture was stirred for 1 hour at40° C. and allowed to cool to ambient temperature and stirred for afurther 18 hour. The mixture was poured into water (1,500 ml), extractedwith hexane (2×750 ml), and the combined organic phases washed withwater (400 ml) and dried (sodium sulfate). The solvent was evaporatedunder reduced pressure to give a brown gum, 39.7 g, containing a mixtureof exo- and endo-6-tert-butyldimethylsilyloxy-8-benzyl-exo-3-cyano-8-azabicyclo[3.2.1]octane(ratio 7:1)

Stage 4

The product from Stage 3 (15.0 g) was dissolved in dry tetrahydrofuran(100 ml) containing 3,5-dichloropyridine (4.30 g) at 0° C. under anatmosphere of nitrogen with stirring. Lithium bis-(trimethylsilyl) amide(38.0 ml of a tetrahydrofuran solution, 1M) was added dropwise to thesolution over 1 hour, maintaining the reaction temperature below 5° C.The reaction was allowed to warm to ambient temperature and stirred for18 hours. The reaction mixture was treated with further lithiumbis-(trimethylsilyl)amide (7.0 ml of a tetrahydrofuran solution, 1M)added dropwise over 2 hours at ambient temperature, stirred for 6 hoursand stored for 18 hours. The mixture was poured into water (500 ml),extracted with hexane (2×400 ml), the combined organic phase was washedwith water, dried (sodium sulfate) and evaporated under reduced pressureto give a brown oil, 18.5 g. The oil was fractionated by chromatography(silica, hexane/ethyl acetate 10:1 by volume) to give8-benzyl-exo-6-tert-butyldimethylsilyloxyxo-3-(5-chloropyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane,yellow oil, 7.8 g.

¹H NMR (CDCl₃): δ0.15(6H,two s); 0.90(9H,s); 2.19-2.40(5H,m); 2.80-2.90(1H,q); 3.30(1H,m); 3.60( 1H,m); 3.90-4.10(2H,q); 5.05(1H,dd);7.20-7.45(5H,m); 7.80(1H,t); 8.55(1H,d); 8.70(1H,d)ppm.

Stage 5

The product from Stage 4 (4.92 g) was dissolved in tetrahydrofuran (20ml) with stirring, aqueous hydrochloric acid (30 ml, 4M) added and themixture stirred at ambient temperature for 18 hours and stored for 3days. The mixture was diluted with water, extracted with ethyl acetate(three times) and the acidic aqueous phase separated and basified withsodium carbonate. The aqueous basic phase was extracted withdichloromethane (three times), dried (magnesium sulfate) and evaporatedunder reduced pressure to giveexo-3-(5-chloropyrid-3-yl)-endo-3-cyano-exo-6-hydroxy-8-benzyl-8-azabicyclo[3.2.1]octaneas an off-white solid, 2.71 g, mp 162.5-164.5° C.

¹H NMR (CDCl₃): δ2.00(1H,d); 2.10-2.40(4H,m); 2.95(1H,q); 3.40(1H,m);3.60(1H,m); 4.00(2H,q); 5.05(1H,m); 7.20-7.40(5H,m); 7.85(1H,t);8.55(1H,d); 8.70(1H,d)ppm.

Stage 6

The product from Stage 5 (2.61 g) was suspended in dichloromethane (30ml) containing 4-dimethylaminopyridine (0.99 g) with stirring at ambienttemperature. 4-Tolyl chlorothionoformate (1.25 ml) was added dropwiseand the reaction mixture stirred at ambient temperature for 18 hours.The mixture was poured into water, extracted with dichloromethane (threetimes), the combined organic phase dried (magnesium sulfate) andevaporated under reduced pressure to give a brown oil containingexo-3-(5-chloropyrid-3-yl)-endo-3-cyano-exo-6-(thiono-4-tolyloxy)-8-benzyl-8-azabicyclo[3.2.1]octane,which was used in Stage 7 without further purification.

Stage 7

The product from Stage 6 (4.5 g) was dissolved in xylene (40 ml, dry)and heated to 160° C. for 18 hours under an atmosphere of nitrogen withstirring. The reaction was cooled to ambient temperature, treated withaqueous hydrochloric acid (2M) until strongly acidic and extracted withethyl acetate (three times). The aqueous acidic phase was separated,basified with sodium carbonate, extracted with ethyl acetate (threetimes) and the organic phases combined and dried (magnesium sulfate).The solvent was evaporated under reduced pressure to give the requiredproduct as an off-white solid, 2.20 g. A portion, (0.2 g), wasfractionated by thick layer chromatography (silica; hexane/ethyl acetate1:1 by volume) to give an analytically pure sample ofexo-3-(5-chloropyrid-3-yl)-ndo-3-cyano-8-benzyl-8-azabicyclo[3.2.1]oct-6-ene, (0.15 g), colourless solid, mp 130-1° C.

¹H NMR (CDCl₃): δ2.20-2.40(4H,m); 3.60(2H,s); 3.75(2H,m); 6.30(2H,s);7.20-7.40(5H,m); 7.85(1H,t); 8.55(1H,d); 8.75(1H,d)ppm.

Stage 8

Acetic-formic mixed anhydride (prepared from acetic anhydride and sodiumformate) was added to the product from Stage 7 (0.10 g) dissolved indichloromethane (2 ml, dry) containing N,N-diisopropylethylamine (0.078ml) and the mixture stirred at ambient temperature for 2 hours. Themixture was poured into a solution of aqueous sodium carbonate (20 ml),extracted with ethyl acetate (2×20 ml). The organic extracts werecombined, dried (magnesium sulfate) and evaporated under reducedpressure to give the required product as a colourless solid, mp 151-4°C.

¹H NMR (CDCl₃): δ2.15-2.50(4H,m); 4.75(1H,m); 5.20(1H,m); 6.50(2H,s);7.80(1H,t); 8.30(1H,d); 8.45(1H,brd); 8.55(1H,brd)ppm.

EXAMPLE 2

This Example illustrates the preparation ofexo-3-(5-methoxypyrid-3-yl)endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane(Compound No. 2 Table I).

exo-3-(5-Methoxypyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.05g) was added to 90% fornic acid (1 ml) and the mixture heated at 110° C.for 24 hours. After cooling to room temperature the mixture wasevaporated under reduced pressure, toluene (2×5 ml) added and themixture evaporated under reduced pressure. The mixture was added to 100%formic acid (2 ml) and heated at 90° C. for 18 hours. The mixture wasthen evaporated under reduced pressure, dilute sodium carbonate (0.5 ml)added and the mixture extracted with ethyl acetate (×2). The combinedextracts were evaporated under reduced pressure and preparative thinlayer chromatographed [SiO₂; ethyl acetate:methanol (90:10)] to giveexo-3-(5-methoxypyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane (0.006 g) mp 134-136° C.

¹H NMR (270 MHz) CDCl₃: δ8.35 (1H, d), 8.30(1H,d), 8.20(1H,s),7.25(1H,t), 4.85(1H,m), 4.30(1H,m), 3.90(3H,s) and 2.6-2.1(8H,m)ppm.

EXAMPLE 3

This Example illustrates the preparation ofexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane (Compound No. 3 Table I).

Vinyl chloroformate (4.2 ml) was added toexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (5.0 g) in dry tetrahydrofuran (50ml) at 0° C. The mixture was refluxed for 3 hours and allowed to standat room temperature overnight. Water and ethyl acetate were added andthe organic phase separated, washed with saturated sodium bicarbonate,dried (MgSO₄) and evaporated under reduced pressure to giveexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (6.2 g, not pure) mp 63-66° C.

Concentrated hydrochloric acid (5 ml) was added to a mixture ofexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (4.08 g) inmethanol (100 ml). The mixture was refluxed for 1 hour, allowed to standat room temperature for 18 hours and evaporated under reduced pressure.Acid/base extraction gaveexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (2.77g) mp 135-137° C.

Formic acetic anhydride (0.4 g) was added dropwise to a stirred solutionof exo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-azabicyclo[3.2.1 ]octane(0.52 g) in diethyl ether (400 ml) at room temperature. After 30 minutesthe mixture was evaporated under reduced pressure to a volume ofapproximately 100 ml at which point a precipitate formed which wasfiltered to giveexo-3-(5-bromopyrid-3-yl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane(0.295 g) mp 146-148° C.

¹H NMR (270 MHz) CDCl₃: δ8.65(2H,m), 8.19(1H,s), 7.89(1H,t), 4.86(1H,m), 4.32(1H,m) and 2.6-2.1(8H,m)ppm.

EXAMPLE 4

This Example illustrates the preparation ofexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane (Compound No. 4 Table I).

Vinyl chloroformate (2.8 ml) in tetrahydrofuran (10 ml) was addeddropwise to a solution ofexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-methyl-8-azabicyclo[3.2.1]octane (5.7 g) in tetrahydrofuran (25 ml) at 0° C. under nitrogen. Themixture was heated at 50° C. for 3 hours and then cooled and filtered.The filtrate was washed with brine, dried (MgSO₄) and evaporated underreduced pressure to giveexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1 ]octane (5.7 g).

exo-3-(3,5-Difluorophenyl)-endo-3-cyano-8-(vinyloxycarbonyl)-8-azabicyclo[3.2.1]octane (5.7 g) andconcentrated hydrochloric acid (5 m) were heated under reflux inmethanol (70 ml) for 4 hours. The mixture was then cooled to roomtemperature, basified with 2M sodium hydroxide and extracted withdichloromethane. The combined extracts were washed with brine, dried(MgSO₄) and evaporated under reduced pressure. Chromatography [SiO₂;dichloromethane:methanol (90:10)] gaveexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (2.85g) mp 112° C.

Formic acetic anhydride (0.46 g) was added dropwise to a stirredsolution of exo3-(3,5-difluorophenyl)-endo-3-cyano-8-azabicyclo[3.2.1]octane (0.516 g) in diethyl ether (35 ml) at room temperature undernitrogen. After 20 minutes the mixture was allowed to stand overnightand then filtered. The filtrate was slowly evaporated and a precipitateformed. Filtration gaveexo-3-(3,5-difluorophenyl)-endo-3-cyano-8-formyl-8-azabicyclo[3.2.1]octane(0.22 g) mp 146° C.

¹H NMR (270 MHz) CDCl₃: δ8.19(1H,s), 7.00(2H,m), 6.79(1H,m), 4.82(1H,m),4.30(1H,m) and 2.6-2.1(8H,m)ppm.

EXAMPLE 5

This Example illustrates an emulsifiable concentrate composition whichis readily convertible by dilution with water into a liquid preparationsuitable for spraying purposes. The concentrate has the followingcomposition:

% Weight Compound No. 1 25.5 SYNPERONIC NP13 2.5 Calciumdodecylbenzenenesulphonate 2.5 AROMASOL H 70

EXAMPLE 6

This Example illustrates a wettable powder composition which is readilyconvertible by dilution with water into a liquid preparation suitablefor spraying purposes. The wettable powder has the followingcomposition:

% Weight Compound No. 1 25.0 Silica 25.0 Sodium lignosulphonate 5.0Sodium lauryl sulphate 2.0 Kaolinite 43.0

EXAMPLE 7

This Example illustrates a dusting powder which may be applied directlyto plants or other surfaces and comprises 1% by weight of Compound No. 2and 99% by weight of talc.

EXAMPLE 8

This Example illustrates a concentrated liquid formulation suitable forapplication by ultra low volume techniques after mixing with paraffinicdiluents.

% Weight Compound No. 2 90.0 SOLVESSO 200 10.0

EXAMPLE 9

This Example illustrates a capsule suspension concentrate which isreadily convertible by dilution with water to form a preparationsuitable for application as an aqueous spray.

% Weight Compound No. 3 10.0 Alkylbenzene solvent (e.g. AROMASOL H) 5.0Toluene di-isocyanate 3.0 Ethylenediamine 2.0 Polyvinyl alcohol 2.0Bentonite 1.5 Polysaccharide (e.g. KELTROL) 0.1 Water 76.4

EXAMPLE 10

A ready for use granular formulation:

% Weight Compound No. 4 0.5 SOLVESSO 200 0.2 nonylphenol ethoxylate (egSynperonic NP8) 0.1 Calcium carbonate granules (0.3-0.7 mm) 99.2

EXAMPLE 11

An aqueous suspension concentrate:

% Weight Compound No 4 5.0 Kaolinite 15.0 Sodium lignosulphonate 3.0nonylphenolethoxylate (eg Synperonic NP 8) 1.5 propylene glycol 10.0Bentonite 2.0 Polysaccharide (eg Keltrol) 0.1 Bactericide (eg Proxel;Proxel is a registered Trade Mark) 0.1 Water 63.3

EXAMPLE 12

This Example illustrates a water dispersible granule formulation.

% Weight Compound No. 2 5 Silica 5 Sodium lignosulphate 10 Sodiumdioctylsulphosuccinate 5 Sodium acetate 10 Montmorillonite powder 65

EXAMPLE 13

This Example illustrates the insecticidal properties of the compounds offormula (I). The activity of the compounds of formula (I) was determinedusing a variety of pests. The pests were treated with a liquidcomposition containing 500 parts per million (ppm) by weight of thecompound unless otherwise stated. The compositions were made bydissolving the compound in acetone and ethanol (50:50) mixture anddiluting the solutions with water containing 0.05% by weight of awetting agent sold under the trade name “SYNPERONIC” NP8 until theliquid composition contained the required concentration of the compound.“SYNPERONIC” is a Registered Trade Mark.

The test procedure adopted with regard to each pest was basically thesame and comprised supporting a number of the pests on a medium whichwas usually a substrate, a host plant or a foodstuff on which the pestsfeed, and treating either or both the medium and the pests with thecompositions. The mortality of the pests was then assessed at periodsusually varying from two to five days after the treatment.

The results of the tests against peach aphid (Myzus Mersicae) arepresented below. The results indicate a grading of mortality (score)designated as A, B or C wherein C indicates less than 40% mortality, Bindicates 40-79% mortality and A indicates 80-100% mortality. In thistest Chinese cabbage leaves were infested with aphids, the infestedleaves were sprayed with the test composition, and the mortalityassessed after 3 days. Compound Nos. 1, 2 and 3 of Table I and gave amortality score of A.

The formula referred to hereinabove are set out as follows

What is claimed is:
 1. A compound of formula (I):

wherein A is CH₂—CH₂ or CH═CH; and Ar is pyridinyl optionallysubstituted with cyano, alkyl, alkenyl, alkynyl or alkoxy; or an acidaddition salt, quaternary ammonium salt or N-oxide derived therefrom. 2.A compound of formula (I) as claimed in claim 1 wherein A is CH═CH.
 3. Acompound according to claim 1 wherein Ar is pyridinyl optionallysubstituted with cyano, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or C₁₋₄alkoxy.
 4. A compound according to claim 1 wherein Ar is pyridinyloptionally substituted with cyano, C₁₋₄ alkyl, C₂₋₄ alkynyl or C₁₋₄alkoxy.
 5. A compound according to claim 1 wherein Ar is 3-pyridinyloptionally substituted at the 5 -position with C₁₋₄ alkyl, C₂₋₄ alkynylor C₁₋₄ alkoxy.
 6. An insecticidal, acaricidal or nematicidalcomposition comprising an insecticidally, acaricidally or nematicidallyeffective amount of a compound of formula (I) according to claim 1, anda suitable carrier or diluent therefore.
 7. A method of combating andcontrolling insect, acarine or nematode pests at a locus which comprisestreating the pests or the locus of the pests with an effective amount ofa compound according to claim
 1. 8. A method according to claim 7wherein the pests are insect pests of growing plants.
 9. A process forpreparing a compound of formula (I) as claimed in claim 1 comprisingreacting a compound of formula (II):

with either formic acid at an elevated temperature or with a mixedformic anhydride.
 10. A method of combating and controlling insect,acarine or nematode pests at a locus which comprises treating the pestsor the locus of the pests with an effective amount of a compositionaccording to claim 6.